59cartilage as it is intimately involved in the pathogenesis of osteoarthritis (OA) , and
the last section of this chapter will focus specifi cally on articular cartilage healing.
While the high matrix-to-cell ratio of cartilage tissue underlies its mechanical proper-ties, it also is responsible for its poor intrinsic healing capacities. In addition to being
hypocellular, healthy adult cartilage is also avascular. Thus, injured cartilage has very
few reserve chondrocytes available to synthesize new matrix. The chondrocytes that are
present are trapped in their lacunae and embedded in dense cartilaginous matrix , making
migration to wound sites diffi cult. Similarly, the lack of blood vessels also presents a
barrier for stem cells from other parts of the body to reach the injured cartilage. Once
cartilage tissue structure is compromised by a wound, the important nutrient transport
environment begins to break down, causing loss of additional chondrocytes and carti-
lage tissue. Thus, rather than healing, even minor cartilage injuries can result in positive
feedback scenarios in which large areas of cartilage are lost and do not regrow. Here we
will examine special cases in the animal kingdom where cartilage does, in fact, naturally
regenerate, as well as strategies for the therapeutic enhancement of cartilage healing.
4.2 Cartilage Formation During Embryonic Development
and Adult Fracture Healing
Cartilage is initially formed in vertebrates during embryonic development of the
skeletal system [ 3 ]. In fact, the early skeleton is entirely made up of cartilage, and
cartilage cell sources vary with body location. For example, cartilage of the head is
formed from the neural crest. Cartilage of the neck and trunk forms as part of the
axial skeleton from the sclerotome of paraxial mesoderm, while cartilage of the tail
skeleton originates from tail bud mesenchyme. Limb cartilage originates with the
appendicular skeleton from lateral plate mesoderm. In the earliest stages of chon-
drogenesis , mesenchymal cells aggregate and condense in response to signaling
molecules such as transforming growth factor-β (TGFβ) , sonic hedgehog (SHH) ,
and bone morphogenetic protein (BMP). Upon commitment to chondrogenesis ,
cells express the transcription factor Sox-9 , which drives expression of cartilage-
specifi c genes, including the matrix proteins Col2 and aggrecan. In vertebrates that
undergo skeletal ossifi cation , the cartilaginous skeleton acts as a template for the
eventual replacement with bone, a process known as endochondral ossifi cation.
Chondrocytes cease proliferating and undergo hypertrophy. This critical milestone
in the process of endochondral ossifi cation is typifi ed by characteristic changes in
chondrocyte morphology , including dramatic increases in cell volume, and a defi ned
gene expression profi le. Hypertrophic chondrocytes begin secreting a unique matrix
consisting of collagen type X and alkaline phosphatase , which initiates matrix cal-
cifi cation [ 4 – 6 ]. The hypertrophic chondrocytes also begin secreting the protease ,
matrix metalloproteinase-13 (MMP-13) [ 7 – 10 ], that breaks down cartilage matrix,
and growth factors such as vascular endothelial growth factor (VEGF) [ 11 ], which
induces blood vessels to sprout from the surrounding tissues. The hypertrophic
chondrocytes then undergo apoptosis and are replaced by mesenchymal cells and
pre-osteoblasts brought into the cartilage template via invading capillaries [ 12 – 15 ].
4 Cartilage Healing, Repair, and Regeneration: Natural History to Current Therapies